WO2012006081A1 - Formulation orale d'inhibiteurs de kinases - Google Patents

Formulation orale d'inhibiteurs de kinases Download PDF

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Publication number
WO2012006081A1
WO2012006081A1 PCT/US2011/042162 US2011042162W WO2012006081A1 WO 2012006081 A1 WO2012006081 A1 WO 2012006081A1 US 2011042162 W US2011042162 W US 2011042162W WO 2012006081 A1 WO2012006081 A1 WO 2012006081A1
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WO
WIPO (PCT)
Prior art keywords
formulation
kinase inhibitor
polyethylene glycol
oil
peg
Prior art date
Application number
PCT/US2011/042162
Other languages
English (en)
Inventor
Andrew Xian Chen
Yali J. Tsai
Original Assignee
Poniard Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Poniard Pharmaceuticals, Inc. filed Critical Poniard Pharmaceuticals, Inc.
Priority to CN201180042122.1A priority Critical patent/CN103313697B/zh
Priority to CA2803004A priority patent/CA2803004A1/fr
Priority to AU2011276552A priority patent/AU2011276552B2/en
Priority to MX2012014982A priority patent/MX340819B/es
Priority to JP2013518572A priority patent/JP5936609B2/ja
Priority to NZ604583A priority patent/NZ604583A/en
Priority to EP11804122.7A priority patent/EP2588081A4/fr
Publication of WO2012006081A1 publication Critical patent/WO2012006081A1/fr
Priority to ZA2013/00009A priority patent/ZA201300009B/en
Priority to US13/967,270 priority patent/US9375402B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom

Definitions

  • Focal Adhesion Kinase a family known as Focal Adhesion Kinase.
  • Focal adhesion kinase has recently been established as a key component of the signal transduction pathways triggered by integrins. Aggregation of FAK with integrins and cytoskeletal proteins in focal contacts has been proposed to be responsible for FAK activation. Recent results from a number of different approaches have shown that integrin signaling through FAK leads to increased cell migration on fibronectin as well as potentially regulating cell proliferation and survival. JL Guan (1997 Aug-Sep), Int J Biochem Cell Biol., 29(8-9):1085-96.
  • FAK focal adhesion kinase
  • Certain compounds of the 2,4-diaminopyridine class of inhibitors show promise in the treatment of malconditions that may be affected by FAK, such as proliferative disorders such as cancer and inflammatory disorders such as arthritis. See, for example, published PCT application WO2008/115369, wherein compounds of this type are disclosed.
  • such compounds must be formulated to provide adequate pharmacokinetic properties, such as AUC.
  • Oral administration of compounds is generally preferred by the patient population, so oral formulations providing favorable pharmacokinetics are needed.
  • the invention is directed to formulations of kinase inhibitors, such as small-molecule inhibitors of Focal Adhesion Kinase, adapted for oral administration to patients.
  • the oral formulations are self-emulsifying formulations adapted to provide favorable pharmacokinetic properties for compound often of limited water solubility.
  • the invention provides an oral formulation for administration of a kinase inhibitor, comprising
  • the invention provides a method for treatment of a malcondition in a patient wherein inhibition of a kinase is medically indicated, comprising orally administering to the patient an effective amount the formulation of the invention in a dose, at a frequency and for a duration of time to provide a beneficial effect to the patient.
  • the invention provides a method of preparing the formulation of the invention, comprising combining the kinase inhibitor and the solubilizing agent and, optionally, an organic solvent, then combining with the oil and the surfactant.
  • mammals as used herein, “individual” (as in the subject of the treatment) means both mammals and non-mammals. Mammals include, for example, humans; non-human primates, e.g. apes and monkeys; and non-primates, e.g. dogs, cats, cattle, horses, sheep, and goats. Non-mammals include, for example, fish and birds.
  • FAK Focal Adhesion Kinase
  • administering refers to providing a medicinal compound to a patient in need thereof.
  • a “dose” is the amount of the active pharmaceutical ingredient (API), in this case picoplatin, that is provided in a single administration.
  • a “frequency” of administration refers to how often the medication is given when repeated doses are prescribed; for example, the medication can be administered daily.
  • a “duration” refers to the period of time over which repeated doses are administered; for example, the picoplatin can be administered for a duration of two weeks.
  • an effective amount when used to describe therapy to an individual suffering from a disorder, refers to the amount of a compound of the invention that is effective to inhibit or otherwise act on FAK in the individual's tissues wherein FAK involved in the disorder is active, wherein such inhibition or other action occurs to an extent sufficient to produce a beneficial therapeutic effect.
  • substantially as the term is used herein means completely or almost completely; for example, a composition that is "substantially free” of a component either has none of the component or contains such a trace amount that any relevant functional property of the composition is unaffected by the presence of the trace amount, or a compound is "substantially pure” is there are only negligible traces of impurities present.
  • Treating refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder, or curing the disease or disorder.
  • an "effective amount” or a “therapeutically effective amount” of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects.
  • a “formulation” as the term is used herein is a composition of matter including picoplatin and other components, such as excipients, stabilizers, dispersants, surfactants, and the like.
  • Self-emulsifying refers to a property of a formulation wherein upon contacting the formulation with an aqueous medium, such as in the
  • the formulation spontaneously forms an emulsion.
  • an “oil” as the term is used herein refers to an organic liquid, which is water-insoluble, or at least only partially water-soluble, that can form a separate phase in the presence of water.
  • An example of an "oil” is a glyceride such as a medium chain triglyceride, or a medium chain mono- or di-glyceride, or castor oil.
  • Another example of an oil is a fatty ester.
  • a fatty ester refers to an alkyl ester of a fatty acid.
  • An example is ethyl oleate.
  • “MCT oil” refers to medium chain triglyceride oil. Examples include the MCT oil sold under the Miglyol trademark, such as Miglyol 912, a caprylate/caprate ( octanoate/decanoate triglyceride).
  • Miglyol 812 (Sasol Germany GmbH, Witten, Germany) refers to a medium chain triglyceride wherein the acid moieties are caprylic and capric acid. Miglyol is a trademark identifying the source of this and other varieties of MCT oil.
  • Capmul MCM is a glyceryl caprate / caprylate ester.
  • “Labrafil M 2125” is a linoleoyl PEG-glyceride, i.e., a linoleic ester of PEG-ylated glycerol.
  • a "surfactant” as the term is used herein is a substance that reduces interfacial surface tension between immiscible liquids such as oil and water, reduces surface tension of a water drop, and exhibits other surface-active properties as are well known in the art. Surfactants are also known as
  • weight average molecular weight is well known in the art and characterizes an average molecular weight of a polydisperse sample of a polymer.
  • a "PEG” or a “polyethyleneglycol” is a polymeric material composed of repeating -CH 2 CH 2 O- units, wherein there are two or more units.
  • diethyleneglycol and all higher polymers are polyethyleneglycols within the meaning herein.
  • a polyethyleneglycol can have a free OH group at either terminus or at both termini, or can alternatively include other groups such as an ether group at one or both ends, for example a dimethyl ether
  • PEG-400 is a PEG with a weight average molecular weight of about 400 DA.
  • PEG-8000 is a PEG with a weight average molecular weight of about 8000 DA.
  • a compound can be "PEG-ylated", meaning that it bears at least one PEG group, which can be introduced in a variety of ways, such as by
  • Polysorbate 80 refers to sorbitan mono-9-octadecanoate
  • poly(oxy-l,2-ethanediyl) derivatives are well known as complex mixtures of polyoxyethylene ethers used as emulsifiers or dispersing agents in
  • Sodium Lauryl Sulfate is sodium dodecyl sulfate, a well known commercially available surfactant.
  • Phospholipon 90G or “PL90G” (American Lecithin Products, Oxford, CT) is a tradename for lecithin, minimum 94% phosphatidylcholine for the manufacture of liposomes.
  • Phospholipon 90H or “PL90H” is a hydrogenated PL90G.
  • the term “PL90” refers to either one of these materials.
  • Vitamin E TPGS refers to the compound D-alpha-tocopheryl polyethylene glycol 1000 succinate.
  • the invention provides an oral formulation for administration of a kinase inhibitor, comprising (a) the kinase inhibitor in pharmaceutically acceptable form;
  • the formulation can comprise about 0.01 wt% to about 20 wt% of the kinase inhibitor. More specifically, the formulation can comprise about 2 wt% to about 7 wt% of the kinase inhibitor.
  • the kinase inhibitor can be of formula (I)
  • R 1 is alkyl, aryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
  • R 2 , R 3 3 and R 4 are each independently alkyl, aryl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, or fluoro;
  • R 5 is hydrogen, alkyl, aryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; w is 1 to 4;
  • x 1 to 3;
  • y is 1 to 2;
  • z 1 to 4.
  • the kinase inhibitor can be of the formula
  • the formulation can comprise about 20 wt% to about 80 wt% of the oil.
  • the oil can be a composition selected from the set consisting of a medium chain triglyceride wherein the acid moieties are caprylic and capric acid(such as Migloyl 812), a glyceryl caprate / caprylate ester (such as Capmul MCM), a linoleoyl PEG-glyceride (such as Labrafil M 1944 CS), castor oil, and oleic acid.
  • the oil is a glyceryl caprate / caprylate ester such as Capmul MCM.
  • the formulation can comprise about 5 wt% to about 50 wt% of the solubilizer.
  • the solubilizer can comprise ethanol, isopropanol, propylene glycol, PEG 400, or glycerol, or any combination thererof; optionally additionally comprising sodium lauryl sulfate (sodium dodecyl sulfate), polysorbate 80 (sorbitan mono-9-octadecanoate poly(oxy-l,2-ethanediyl) derivatives), or a combination thereof.
  • the solubilizer comprises PEG 400, for example the formulation can comprise up to about 10% PEG 400.
  • the formulation can comprise about 5 wt% to about 50 wt% of the surfactant.
  • the surfactant can comprises a lecithin such as Phospholipon 90G, an alpha-tocopheryl polyethylene glycol 1000 succinate (Tocopheryl polyethylene glycol 400), or any combination thereof.
  • the surfactant can comprise a mixture a lecithin such as Phospholipon 90G and an alpha-tocopheryl polyethylene glycol 1000 succinate such as Tocopheryl polyethylene glycol 400. More specifically, the surfactant comprise an approximately 1 : 1 mixture of a lecithin such as Phospholipon 90G and an alpha-tocopheryl polyethylene glycol 1000 succinate such as Tocopheryl polyethylene glycol 400.
  • a formulation of the invention can comprise about 2 wt% to about 5 wt% of the kinase inhibitor, about 35-50 wt% of a glyceryl caprate / caprylate ester (such as Capmul MCM), about 20-40 wt% of a lecithin such as Phospholipon 90G, about 15-30 wt% of an -alpha-tocopheryl polyethylene glycol 1000 succinate such as Tocoperyl polyethylene glycol 1000 succinate, and up to about 10% PEG 400.
  • a glyceryl caprate / caprylate ester such as Capmul MCM
  • a lecithin such as Phospholipon 90G
  • an -alpha-tocopheryl polyethylene glycol 1000 succinate such as Tocoperyl polyethylene glycol 1000 succinate
  • up to about 10% PEG 400 up to about 10% PEG 400.
  • the kinase inhibitor can be present in a formulation of the invention in free base form.
  • the kinase inhibitor can be a pharmaceutically acceptable salt of the inhibitor, such as a hydrochloride salt.
  • the kinase inhibitor can be SR3721, SR2516, or SR3406, the structures of which are shown below.
  • the formulation can be self-emulsifying in an aqueous medium.
  • the formulation can be self-emulsifying in the gastrointestinal tract of a patient ingesting the formulation.
  • a formulation of the invention upon oral ingestion by a patient, can increase the pharmacokinetic parameter Area Under the Curve (AUC) in the patient relative to the AUC for a comparable dose of the same kinase inhibitor orally administered in a non-self-emulsifying formulation.
  • AUC Area Under the Curve
  • the invention provides a method for treatment of a malcondition in a patient wherein inhibition of a kinase is medically indicated, comprising orally administering to the patient an effective amount the formulation of the invention in a dose, at a frequency and for a duration of time to provide a beneficial effect to the patient.
  • the malcondition comprises a proliferative disorder such as cancer or an
  • inflammatory disorder such as arthritis.
  • the invention provides the use of a formulation of the invention for treatment of a malcondition.
  • the malcondition can comprise a proliferative disorder such as cancer or an inflammatory disorder such as arthritis.
  • the invention provides a method of preparing a formulation of the invention, the method comprising combining the kinase inhibitor and the solubilizing agent and, optionally, an organic solvent, then combining with the oil and the surfactant.
  • This purpose of this study was to select an oil / surfactant system(s) capable dissolving SRs to the target concentration
  • This purpose of this study was to evaluate the stability of SR-261 and SR-3406 at 5% in F-1 formulation for up to 2 weeks.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des formulations de composés bioactifs à solubilité limitée dans l'eau, d'inhibiteurs de kinases d'adhésion focale (FAK) de la classe 2,4-diaminopyridine, adaptées pour une administration par voie orale à des patients. Les formulations sont auto-émulsifiantes dans le tractus gastro-intestinal des patients, permettant une absorption et une biodisponibilité accrues des composés bioactifs sous forme de dispersions ou émulsions dans une base huileuse. Par exemple, des esters de glycérol PEG-ylé peuvent être utilisés comme huile, en conjonction à des tensio-actifs, tels que la lécithine et le succinate de TEPG, et à des agents solubilisants, tels que le PEG 400, afin de fournir des formulations orales utiles pour l'administration à des patients présentant un état dans lequel l'inhibition de FAK est médicalement indiquée, tel que le cancer ou l'arthrite.
PCT/US2011/042162 2010-06-29 2011-06-28 Formulation orale d'inhibiteurs de kinases WO2012006081A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
CN201180042122.1A CN103313697B (zh) 2010-06-29 2011-06-28 激酶抑制剂的口服制剂
CA2803004A CA2803004A1 (fr) 2010-06-29 2011-06-28 Formulation orale d'inhibiteurs de kinase
AU2011276552A AU2011276552B2 (en) 2010-06-29 2011-06-28 Oral formulation of kinase inhibitors
MX2012014982A MX340819B (es) 2010-06-29 2011-06-28 Formulacion oral de inhibidores de quinasa.
JP2013518572A JP5936609B2 (ja) 2010-06-29 2011-06-28 キナーゼインヒビターの経口製剤
NZ604583A NZ604583A (en) 2010-06-29 2011-06-28 Oral formulations of kinase inhibitors
EP11804122.7A EP2588081A4 (fr) 2010-06-29 2011-06-28 Formulation orale d'inhibiteurs de kinases
ZA2013/00009A ZA201300009B (en) 2010-06-29 2013-01-02 Oral formulation of kinase inhibitors
US13/967,270 US9375402B2 (en) 2010-06-29 2013-08-14 Oral formulations of kinase inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US35969410P 2010-06-29 2010-06-29
US61/359,694 2010-06-29

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US13807638 A-371-Of-International 2011-06-28
US13/967,270 Continuation US9375402B2 (en) 2010-06-29 2013-08-14 Oral formulations of kinase inhibitors

Publications (1)

Publication Number Publication Date
WO2012006081A1 true WO2012006081A1 (fr) 2012-01-12

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PCT/US2011/042162 WO2012006081A1 (fr) 2010-06-29 2011-06-28 Formulation orale d'inhibiteurs de kinases

Country Status (10)

Country Link
US (1) US9375402B2 (fr)
EP (1) EP2588081A4 (fr)
JP (1) JP5936609B2 (fr)
CN (1) CN103313697B (fr)
AU (1) AU2011276552B2 (fr)
CA (1) CA2803004A1 (fr)
MX (1) MX340819B (fr)
NZ (1) NZ604583A (fr)
WO (1) WO2012006081A1 (fr)
ZA (1) ZA201300009B (fr)

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US9012461B2 (en) 2011-02-17 2015-04-21 Cancer Therapeutics Crc Pty Ltd FAK inhibitors
US9120761B2 (en) 2011-02-17 2015-09-01 Cancer Therapeutics Crc Pty Ltd Selective FAK inhibitors
US9668974B2 (en) 2012-05-10 2017-06-06 Painreform Ltd. Depot formulations of a local anesthetic and methods for preparation thereof

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Publication number Priority date Publication date Assignee Title
US9012461B2 (en) 2011-02-17 2015-04-21 Cancer Therapeutics Crc Pty Ltd FAK inhibitors
US9120761B2 (en) 2011-02-17 2015-09-01 Cancer Therapeutics Crc Pty Ltd Selective FAK inhibitors
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US9668974B2 (en) 2012-05-10 2017-06-06 Painreform Ltd. Depot formulations of a local anesthetic and methods for preparation thereof
US9849088B2 (en) 2012-05-10 2017-12-26 Painreform Ltd. Depot formulations of a hydrophobic active ingredient and methods for preparation thereof
US10206876B2 (en) 2012-05-10 2019-02-19 Painreform Ltd. Depot formulations of a local anesthetic and methods for preparation thereof

Also Published As

Publication number Publication date
US20140206692A1 (en) 2014-07-24
EP2588081A1 (fr) 2013-05-08
CN103313697A (zh) 2013-09-18
JP2013529686A (ja) 2013-07-22
MX340819B (es) 2016-07-26
US9375402B2 (en) 2016-06-28
CN103313697B (zh) 2016-06-01
EP2588081A4 (fr) 2014-12-10
AU2011276552B2 (en) 2015-09-03
ZA201300009B (en) 2013-09-25
AU2011276552A1 (en) 2013-01-10
JP5936609B2 (ja) 2016-06-22
CA2803004A1 (fr) 2012-01-12
MX2012014982A (es) 2013-07-03
NZ604583A (en) 2015-04-24

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